The gut–heart axis in coronary artery disease: a scoping and narrative review of sex-based microbial and metabolic disparities

This scoping review adhered to the criteria of the Preferred Reporting Items for Scoping Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) [16], and the protocol was registered with the Open Science Foundation [17]. We conducted a scoping review following the PRISMA-ScR guidelines to map current evidence on the interplay between sex differences, coronary artery disease, and gut microbiota. Given the limited number and heterogeneity of studies, no meta-analysis or formal assessment of certainty was performed.

We included observational studies with different designs (cross-sectional, case–control, prospective, and retrospective cohort studies) and intervention studies with baseline data, involving human participants. These studies focused on adults aged 18 years or older diagnosed with any form of CAD and either specifically analyzed for sex differences or included sub-analyses on sex differences from studies not originally focused on this aspect. The studies reported data on gut microbiota composition or its metabolites as an exposure. These included measures of specific bacterial taxa, microbiota diversity, ordination techniques, and the composition of gut microbiota metabolites in serum or plasma, such as TMAO, secondary bile acids, SCFAs, tryptophan, and indole derivatives. Only peer-reviewed original articles published in English were considered eligible. Two reviewers independently screened titles and abstracts, followed by a full-text review of potentially eligible studies. A single reviewer also screened the references of included articles for additional relevant material.

Two reviewers collaboratively developed a comprehensive search strategy. Systematic searches were conducted in PubMed and EMBASE Library, covering all articles published during the last 10 years in these databases up to March 2025. The full search algorithms and criteria are outlined in Appendix 1 for transparency and reproducibility.

Data were extracted at the study level using pre-specified forms. First, study characteristics were documented, including the year of publication, study design (observational, cohort), and demographic details for participants with CAD.

For gut microbiota data, information on composition was recorded, including diversity indices (e.g., alpha diversity, beta diversity) and taxonomic abundance at various levels (e.g., phylum, genus, species). The methods used for analysis, such as 16S rRNA sequencing or shotgun sequencing, were also noted.

Metabolite profiling, focusing on specific metabolites of interest, was documented. These metabolites included SCFA (acetate, propionate, butyrate, valerate), bile acids (primary and secondary free and conjugated bile acids, and minor bile acids reflecting microbiota isomerization activity), tryptophan metabolites (e.g., tryptophan, kynurenine, serotonin, and various indole derivatives), and choline derivatives (choline, trimethylamine, TMAO).

As this work is a scoping review, the focus was on identifying and summarizing the available and not to perform quantitative synthesis. Therefore, no formal power calculations, effect size estimations, or confidence interval analyses were conducted. Observed differences in the included studies are presented descriptively, and no inference regarding clinical significance or statistical significance across studies was attempted.

We examined the relationship between gut microbiota and CAD, with an emphasis on both the microbial composition and the functional effects arising from metabolite production. Our selection criteria favored studies that employed 16S rRNA gene sequencing and whole-genome shotgun metagenomic sequencing, as these methods offer a detailed and broad analysis of the fecal microbiota, in contrast to PCR or culture-based approaches that typically focus on specific taxa [18, 19]. Additionally, we assessed whether the studies compared bacterial diversity between individuals with CAD and healthy controls.

Alpha-diversity (α-diversity) measures the variation of gut microbiota within a single sample, considering both the richness of species and their relative abundance. Beta-diversity (β-diversity), on the other hand, evaluates the differences or similarities in microbial communities between groups, often represented using ordination plots to visualize clustering patterns. Furthermore, bacterial species were categorized according to various characteristics, such as phylogeny, metabolic functions, environmental preferences, morphology, and genetic sequence. Our synthesis of taxonomic data included both differentially abundant and discriminatory taxa.

We summarized the results from targeted and untargeted metabolomics using different mass spectrometry techniques (liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and tandem mass spectrometry) or nuclear magnetic resonance to quantify metabolites derived from the gut microbiota resulting from our literature search [20]. We focused on metabolites directly associated with gut microbiota activity, such as SCFAs, bile acids (BAs), TMAO, and other microbial-derived metabolites.

In this review, we define sex as the biological attributes that distinguish individuals as male or female. These attributes typically arise from chromosomal composition, reproductive anatomy, and hormonal influences, as well as environmental or cultural factors that may affect the expression of phenotypic traits.

Our database search identified 286 potential studies, with 254 remaining after duplicate removal. Following primary screening, 48 studies were selected for full-text review (Fig. 1). Eleven studies met the inclusion criteria: 7 examined gut microbiota composition or metabolite profiles between men and women in CAD and 4 contained sub-analyses. Detailed summaries of study characteristics, results, and methodologies are presented in Table 1. The clinical characteristics are summarized in Table 2.

Garcia-Fernandez et al. examined gut microbiota alterations in a population of stable CAD who followed a strict diet, including 567 men and 112 women compared to a control group [21].

In analyzing gut microbiota diversity according to sex in CAD patients, no significant differences were observed in species richness, as assessed by alpha diversity indices. Pronounced sex-specific differences in beta diversity were observed among individuals with CAD, indicating distinct overall microbial community structures between male and female patients. Moreover, within each sex, comparisons between CAD and non-CAD individuals revealed significant shifts in beta diversity, suggesting that the gut microbiota responds to coronary artery disease in a sex-dependent manner.

Building on these community-level differences, taxonomic analyses reveal that sex differences in gut microbiota composition extend beyond disease states. Even in healthy individuals, men and women display distinct microbial profiles, particularly at the genus and family levels, suggesting an intrinsic influence of sex on microbial ecology [21]. In non-CAD individuals, women exhibit greater abundance of taxa such as Bilophila, UCG_010, and Erysipelotrichaceae, while men are enriched in Alistipes, Barnesiella, Ruminococcus, and numerous taxa from Clostridia. Notably, these sex-based differences become more pronounced in the context of CAD. In CAD patients, women display a microbiota enriched in beneficial or commensal genera including Bifidobacterium, Parabacteroides, and Barnesiella, whereas men show broader and deeper dysbiosis marked by increased levels of pro-inflammatory genera such as Prevotella, Clostridia_UCG_014, Bilophila, and Eubacterium_siraeum_group. Data modeling using random forest classifier further identified seven bacterial taxa that were particularly discriminant between CAD men and women: UBA1819 (Ruminococcaceae), Bilophila, Subdoligranulum, Phascolarctobacterium, Barnesiellaceae, Ruminococcus, and Ruminococcaceae incertae sedis. Among these, Ruminococcus was particularly significant in distinguishing between CAD and non-CAD individuals in both sexes.

These compositional differences are relevant to CAD because many of these taxa are directly linked to inflammatory and immune pathways implicated in atherosclerosis. For example, Prevotella and Bilophila [22, 23], more abundant in men, have been associated with increased pro-inflammatory signaling and disruption of gut barrier integrity, which can promote systemic inflammation and contribute to plaque development and instability. Prevotella species are considered pathobionts with strong pro-inflammatory potential. They can drive mucosal and systemic inflammation by activating Th17 immune responses [24], stimulating Toll-like receptor 2, and inducing cytokines such as IL-1, IL-6, IL-8, and IL-23 from immune and epithelial cells. Prevotella-mediated inflammation promotes neutrophil recruitment and systemic dissemination of inflammatory mediators [25], linking increased abundance of these bacteria to chronic inflammatory conditions and potentially contributing to vascular inflammation relevant for CAD[26]. Similarly, some Clostridia species expanded in men can produce molecules that drive oxidative stress and inflammatory responses in the vasculature [27, 28]. In contrast, taxa enriched in women, such as Bifidobacterium, Ruminococcus, Barnesiella, and Parabacteroides, are generally considered protective: they support gut barrier function, reduce systemic inflammation, and are associated with lower oxidative stress in observational studies. Bifidobacterium species are beneficial commensals with anti-inflammatory and immune-modulating properties [29]. They promote immune homeostasis by upregulating regulatory T cells, maintaining intestinal barrier integrity, and modulating dendritic cell and macrophage activity, while dampening Th2 and Th17 inflammatory programs [30]. Depletion of Bifidobacterium is associated with impaired immune regulation and dysbiosis [31], whereas their presence supports gut and systemic homeostasis[32], which may protect against chronic inflammation relevant to CAD. Table 3 summarizes the key bacterial taxa, their sex-specific associations, and their potential mechanistic roles in CAD.

Several bacterial taxa highlighted in our sex-specific analysis of CAD patients have also been associated with cardiovascular outcomes in human studies. Lactobacillus, although not sex-specific in our review, has been shown to predict both disease severity and MACE in ACS patients, with higher levels associated with lower risk of all-cause death and major adverse cardiac events [33]. Prevotella and Bilophila, enriched in men with CAD in our cohort, are pro-inflammatory taxa that may contribute to systemic inflammation and plaque instability, consistent with observations linking gut dysbiosis and microbiota-derived metabolites such as deoxycholine acid (DCA) to major adverse cardiovascular events (MACE) risk in Acute ST-Segment Elevation Myocardial Infarction (STEMI) patients [34]. While other taxa in our review (e.g., Bifidobacterium, Ruminococcus, Barnesiella, Parabacteroides) are generally considered protective and anti-inflammatory, their presence aligns with findings from the CORDIOPREV study where specific microbiota profiles were predictive of new MACE events in CAD patients [35]. Finally, although subgingival oral microbiota biomarkers were also linked to secondary cardiovascular events, these findings highlight the broader relevance of microbial composition to cardiovascular prognosis, supporting the mechanistic plausibility of sex-specific gut microbial contributions to CAD outcomes [36].

Thus, sex-specific gut microbial composition provides a plausible mechanistic link between biological sex and CAD phenotypes. Men’s microbiota appears skewed toward taxa that promote inflammation and oxidative stress, potentially exacerbating atherogenesis, whereas women’s microbiota is enriched in taxa that may mitigate these processes, representing a protective ecological pattern. These microbiota-driven differences may act alongside hormonal and immune factors to shape the sex-specific trajectory of CAD, highlighting the microbiome as a potential mediator of cardiovascular risk differences between men and women.

TMAO is a bioactive metabolite derived from dietary sources such as phosphatidylcholine, carnitine, and betaine through gut microbial metabolism. Intestinal microbiota convert these precursors into trimethylamine (TMA), which is subsequently oxidized in the liver by flavin monooxygenases (FMO1 and FMO3) to form TMAO [37]. Elevated plasma levels of TMAO have been strongly associated with an increased risk of cardiovascular diseases (CVD), including atherosclerosis [38], myocardial infarction, and stroke. Notably, studies have demonstrated a prognostic link between TMAO and CAD, showing that higher TMAO concentrations predict major adverse cardiovascular events, independent of traditional risk factors [39].

Six studies have examined sex-specific differences in TMAO levels and their potential association with CAD. Baranyi et al. [40] investigated patients with AMI and found that women had significantly higher TMAO levels than men at hospital admission. These levels remained stable in women until the start of cardiac rehabilitation, while men had lower and relatively stable TMAO concentrations throughout. Sex-specific differences in hepatic enzyme expression, particularly higher flavin-containing monooxygenase 3 (FMO3) activity in females, may explain the increased TMAO production observed in women compared to men, as supported by animal studies showing persistent FMO3 expression in females but post-pubertal downregulation in males [41, 42]. In these patients, by the end of cardiac rehabilitation, TMAO levels in women declined to levels comparable to those observed in men, indicating that lifestyle interventions may attenuate early cardiovascular risk in women through modulation of microbial metabolite production. In addition, Lee et al. [43] reported that betaine levels, a TMAO precursor, were significantly higher in men with AMI, suggesting that substrate availability may also influence TMAO metabolism in a sex-specific manner.

In contrast to the acute setting, two studies of stable CAD consistently report higher circulating TMAO levels in men, reinforcing a sex-specific pattern that may be shaped by chronic microbial and metabolic differences. Garcia-Fernandez et al. [44] showed that men with CAD had significantly higher plasma TMAO levels and a greater TMAO/TMA conversion rate compared to women with CAD. Elevated TMAO levels in men were associated with increased carotid atherosclerosis and an altered gut microbiota composition favoring TMA-producing bacteria. TMA levels were similar between men and women with CAD. Non-CVD individuals showed no sex-related differences in TMA, TMAO, or the TMAO/TMA ratio. Sun et al. [45] found that high TMAO levels were significantly associated with CAD risk in older men (≥ 65 years) but not in younger men or in women of any age compared to the control group. No difference in TMAO level is noted between healthy men and CAD men or healthy women and CAD women. Additionally, in male CAD patients, elevated TMAO levels correlated with more severe CAD, suggesting that men, especially older men, are more vulnerable to its adverse cardiovascular effects.

Further nuance is provided by two smaller sub-analyses, which offer additional insights into the sex-specific dynamics of TMAO levels in CAD. Zhou et al. [46] reported a significant negative correlation between TMAO levels and female with CAD (r = –0.39, P = 0.03), reinforcing the observation that women generally have lower TMAO concentrations. However, Adhikari et al. [47] found no significant sex differences in TMAO levels among younger CAD patients regardless of the sex, suggesting that sex-related differences in TMAO may become more pronounced with age and disease progression.

Microbial determinants of TMA production differ by sex [48]. TMA formation depends on bacterial taxa expressing TMA-generating enzymes (cutC/D, cntA/B, yeaW/X), predominantly found in Enterobacteriaceae, Proteobacteria, Clostridia, and related genera [49]. Men with stable CAD consistently exhibit higher abundance of these TMA-producing taxa, whereas women tend to have higher levels of anti-inflammatory, barrier-supporting commensals such as Bifidobacterium [50]. These compositional differences may underlie the higher chronic TMAO concentrations observed in men, given the greater microbial capacity for TMA generation.

Sex hormones influence hepatic TMAO conversion [51, 52]. FMO3 expression displays marked sexual dimorphism, with higher hepatic FMO3 activity in females [53] and post-pubertal downregulation in males. In acute settings such as AMI, this higher FMO3 activity may contribute to higher TMAO levels observed in women. In contrast, during stable disease, microbial TMA production becomes the dominant driver, resulting in higher chronic TMAO levels in men despite lower hepatic FMO3 activity.

TMAO enhances inflammatory, oxidative, and thrombotic pathways relevant to CAD. TMAO promotes activation of the NLRP3 inflammasome, increases pro-inflammatory cytokine release, augments oxidative stress, impairs endothelial nitric oxide signaling, and enhances foam cell formation by upregulating lipid scavenger receptors and disrupting cholesterol homeostasis [54–56]. It also increases platelet reactivity and thrombogenic signaling [57, 58]. These pathways may be more strongly expressed in men, who typically exhibit higher baseline inflammation, greater visceral adiposity, reduced antioxidant capacity, and higher platelet activation, potentially amplifying the pathogenic effects of TMAO. Clinical evidence indicates that higher plasma TMAO levels are associated with adverse cardiovascular outcomes. In community cohorts, such as the Multi-Ethnic Study of Atherosclerosis (MESA), elevated TMAO predicted incident atherosclerotic cardiovascular disease events over long-term follow-up, independent of traditional risk factors [59]. In patients with established CAD, TMAO levels correlate with plaque vulnerability and rupture [8], and higher concentrations are linked to increased risk of MACE during prospective follow-up [38].

Protective commensals more prevalent in women may modulate TMAO-related risk. Higher abundance of Bifidobacterium and other barrier-stabilizing taxa in women may support immune regulation, maintain epithelial integrity, and limit systemic inflammation, thereby attenuating the downstream impact of TMAO even when circulating levels are similar. Such compositional patterns may contribute to sex-specific modulation of TMAO-associated vascular risk.

Bile acids, synthesized in the liver from cholesterol and further metabolized by gut microbiota, play a crucial role in lipid metabolism, inflammation, and cardiometabolic health. Alterations in BA metabolism have been linked to CAD, with some BAs exerting anti-atherosclerotic effects [60].

Bay et al. [61] investigated sex differences in lipidomic and bile acid profiles in CAD patients and found that while women with CAD showed no significant differences in bile acid concentrations compared to healthy women, men with CAD had decreased levels of secondary bile acids, such as glycolithocholic and lithocholic acids compared to healthy men. Similarly, Couch et al. [62] reported lower levels of glycocholic acid, a conjugated primary bile acid, in men with CAD compared to women with CAD. No control group was available for comparison. In the same direction, Lee et al. [43] found that glycocholic acid was elevated in women with AMI.

Secondary BAs such as lithocholic acid (LCA) and DCA, reduced in men with CAD, are primarily produced by gut microbial transformation of primary bile acids. Unconjugated bile acids (like cholic acid (CA), chenodeoxycholic acid (CDCA), DCA, hydrodeoyxcholic acid (HDCA)) are more potent ligands for Farnesoid X Receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) and can directly modulate cholesterol metabolism, inflammation, and vascular signaling. Conjugated bile acids (glyco- or tauro-conjugates) are less potent at FXR/TGR5 but can facilitate bile acid solubility, enterohepatic circulation, and lipid absorption. Lower secondary bile acid levels may therefore reflect reduced microbial conversion capacity in men, consistent with known depletion of microbial diversity and metabolic activity in cardiometabolic disease [63]. Women with CAD do not show comparable reductions; this may reflect a more preserved microbial environment or differences in bile acid flux through classical versus alternative hepatic synthetic pathways.

FXR governs bile acid synthesis via feedback inhibition of CYP7A1 (Cytochrome P450 Family 7 Subfamily A Member 1) and CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) and modulates cholesterol metabolism, inflammatory signaling, and enterohepatic circulation [64]. Given that CDCA is the most potent endogenous FXR agonist, relative increases in CDCA-rich bile acid pools reinforce FXR activity [65], whereas reductions in secondary BAs diminish TGR5 agonism [63, 66]. In men with CAD, lower secondary BAs may shift the pool toward stronger FXR dominance and reduced TGR5 stimulation, creating an imbalance that favors impaired gut–liver signaling and heightened inflammatory susceptibility. Women, who do not show significant depletion of secondary bile acids, may maintain a more balanced FXR–TGR5 activation profile.

TGR5 activation, primarily driven by unconjugated secondary bile acids (LCA > DCA > CDCA > CA)[67], exerts beneficial effects on vascular and metabolic pathways, including GLP-1 secretion[68], enhancement of endothelial nitric oxide production, smooth muscle relaxation, and attenuation of macrophage-mediated inflammation [69, 70]. Reduced availability of these potent TGR5 agonists in men may contribute to diminished anti-inflammatory and vasoprotective signaling. By contrast, preserved levels of secondary bile acids in women could help maintain TGR5-mediated anti-inflammatory tone, potentially mitigating the adverse impact of CAD-associated metabolic stress.

Both FXR and TGR5 exert anti-inflammatory actions in immune cells, including macrophages, dendritic cells [71], and Natural killer T (NKT) cells [72]. A bile acid pool skewed toward reduced TGR5 activation may weaken anti-inflammatory signaling networks, enhancing Interleukin 6 (IL-6), Tumor Necrosis Factor α (TNF-α), and Interferon- γ (IFN-γ) activity [73]. Given the higher baseline systemic inflammation and visceral adiposity in men, diminished TGR5 signaling may amplify inflammatory responses in CAD, while more preserved BA profiles in women may maintain partially protective immunometabolic regulation.

Collectively, the sex-specific patterns observed—men with CAD presenting lower levels of secondary bile acids, women showing relative preservation or even elevation of certain conjugated bile acids—align with a mechanistic model in which men experience a shift toward reduced TGR5 agonism and altered FXR-driven feedback, contributing to a pro-inflammatory and less metabolically adaptive state. Women appear to maintain a more balanced bile acid signaling environment that may buffer against some pathogenic consequences of CAD and acute myocardial injury. Furthermore, females tend to exhibit higher secondary and conjugated bile acids, while men may have lower secondary bile acids but higher levels of certain conjugated primary bile acids depending on age and hormonal status [74–76]. Unconjugated bile acids such as CA, CDCA, DCA, and HDCA have been inversely associated with CAD risk and cardiovascular mortality [77, 78]. These sex-specific bile acid profiles, partly shaped by gut microbiota and hormonal influences, may differentially modulate FXR/TGR5 signaling, lipid metabolism, and inflammatory pathways, suggesting a potential mechanism by which men and women could experience distinct cardiovascular diseases states.

Indole, a degradation product of the amino acid tryptophan, is produced by intestinal bacteria and subsequently absorbed and metabolized in the liver into IS, a key protein-bound uremic toxin. Research suggests that IS contributes to the progression of cardiovascular disease by promoting cardiac fibrosis, inducing endothelial senescence, stimulating vascular smooth muscle cell proliferation, and activating monocytes and macrophages through an oxidative stress-dependent pathway [79].

Couch et al. [62] also found that men with CAD had lower levels of indole-3-lactic acid, a microbial metabolite derived from tryptophan metabolism than women with CAD. Lee et al. [80] explored the relationship between gut-derived uremic toxins and central obesity in CAD patients. They found significant positive correlations between IS, a tryptophan derivative, with measures of central obesity (e.g., waist-to-hip ratio, conicity index, adiposity body shape index) in men with CAD but not in women with CAD. Another study [43] also found that IS levels were lower in CAD patients of both sexes, with a more pronounced reduction in men; however, this sex difference did not reach statistical significance. Since tryptophan derivatives have been implicated in inflammation and cardiovascular health, these differences may contribute to sex-specific disease mechanisms.

IS promotes oxidative stress (via NADPH Oxidase 4 (NOX4) and mitochondrial reactive oxygen species (ROS)), impairs endothelial repair and endothelial nitric oxide synthase activity, activates aryl hydrocarbon receptor (AHR)/NF-κB signaling in monocytes/macrophages, induces pro-inflammatory cytokine release, enhances macrophage foam-cell formation, stimulates vascular smooth muscle cells osteogenic transformation, and increases thrombogenic signaling (tissue factor expression, platelet-leukocyte interactions) [81]. In men—who characteristically display greater visceral adiposity, higher baseline inflammatory tone, and a gut microbiota profile enriched in pro-inflammatory taxa—the association between IS and central obesity may amplify local and systemic oxidative/inflammatory cascades that accelerate atherogenesis, plaque vulnerability, calcification, and thrombosis [81, 82]. By contrast, women in the previously described cohorts tended to retain higher levels of certain indole derivatives and/or have more barrier-supporting commensals (e.g., Bifidobacterium), which could limit intestinal translocation of indole precursors or modulate host responses to IS, thereby attenuating IS-driven vascular injury. Importantly, renal function, disease stage and age modulate circulating IS and may account for some inconsistencies across studies [82].

Clinical evidences show that in patients with stable angina, higher serum IS levels were independently associated with more severe coronary stenosis, higher Agatston calcium scores, modified Gensini scores, and greater numbers of diseased vessels, suggesting a correlation with CAD burden [83]. In acute coronary syndrome (ACS) patients undergoing primary percutaneous coronary intervention, elevated IS levels predicted six-month composite events—including death, myocardial infarction, heart failure hospitalization, and bleeding events—with a hazard ratio of 10.6 (95% CI: 1.63–69.3), independent of conventional risk factors [84]. IS has significant prognostic utility in CAD and ACS, reinforcing its potential role as a clinically relevant biomarker of adverse cardiovascular outcomes.

Overall, the scoping data support a hypothesis in which sex-specific differences in microbial tryptophan metabolism—interacting with adipose distribution and baseline immune state—render men more vulnerable to the pro-oxidative, pro-inflammatory and pro-thrombotic effects of IS, thereby contributing to greater CAD burden and severity in men versus women.

SCFA are microbial-derived metabolites produced through the fermentation of dietary fibers by gut bacteria. The most abundant SCFAs include acetate, propionate, and butyrate, which play essential roles in host metabolism, immune regulation, and cardiovascular health [85].

Liu et al. [86] identified sex-specific differences in gut microbiota-related metabolites in AMI patients. Succinate, a fermentation byproduct of dietary fibers, was a female-specific metabolite in AMI, whereas acetate, a SCFA, was male-specific in AMI patients with pre-existing cardiovascular disease.

Our scoping analysis identified acetate as a male-enriched SCFA in AMI patients with pre-existing cardiovascular disease. This observation may have bidirectional mechanistic implications for sex differences in CAD. On one hand, acetate signaling via the G-protein–coupled receptor GPR43 activates AMPK in plaque macrophages, suppresses macrophage proliferation, reduces ROS production, and limits pro-inflammatory cytokine expression—actions that reduce plaque formation and progression in experimental atherosclerosis models [87]. On the other hand, acetate can be metabolically converted to acetyl–CoA within endothelial cells, enhancing protein acetylation of TGF-β pathway components (Activin receptor-like kinase 5, intracellular mediator of TGF-β/ALK5 signaling (SMADs)) via Acyl-CoA synthetase short-chain family member 2 (ACSS2)-dependent pathways and thereby stabilizing TGF-β signaling and promoting endothelial-to-mesenchymal transition (EndMT), a driver of vascular fibrosis and chronic vascular remodeling [88]. Additionally, acetate-related signaling has been linked to modulation of endothelial pyroptosis pathways through histone deacetylase–related mechanisms in preclinical studies [89]. Taken together, the enrichment of acetate in men with AMI and established CVD may reflect a context-dependent balance: in some vascular cell compartments (macrophages) acetate may exert anti-atherogenic, anti-inflammatory effects, whereas in endothelial metabolic states favoring ACSS2 activity it may promote profibrotic EndMT and maladaptive remodeling. Sex-specific factors—differences in gut microbial composition, substrate availability, endothelial metabolic programming, and hormonal regulation—could shift this balance toward net benefit or harm. Thus, higher acetate in men could contribute both protective and deleterious pathways, potentially explaining part of the sex-specific phenotype in CAD depending on disease stage and cellular context.

While our current data do not specifically report sex-stratified levels of these metabolites in CAD or AMI, emerging literature suggests that sex differences in butyrate-producing bacteria exist and may have cardiometabolic implications. For instance, women have been shown to harbor a higher relative abundance of butyrate-producing genera such as Oscillospiraceae and Lachnospiraceae, along with enriched genes for butyrate synthesis across multiple pathways, compared with men [90]. In animal and human in vitro studies, male microbiotas exhibited lower butyrate production and associated metabolic dysfunction, including increased triglycerides, leptin, and oxidative stress, suggesting sex-specific effects on lipid metabolism [91, 92].

However, these metabolites were not found to be biomarkers to classify between controls and AMI patients. Histidine, a semiessential amino acid with antioxidant and anti-inflammatory properties, also emerged as male-specific in AMI events, and alterations in histidine metabolism were more pronounced in patients with concomitant CVD. Notably, histidine metabolism may be linked to the generation of downstream metabolites such as histamine, glutamate, and glutamine, which have been implicated in AMI pathophysiology [93, 94]. In addition, the microbial metabolite imidazole propionate—derived from histidine rather than fiber fermentation—has been identified as a potential independent risk factor for atherosclerosis, highlighting the need for further studies evaluating its sex-specific effects on CAD [95].

The Fig. 2 is a comprehensive summary of the results and illustrates the interconnected sex-specific differences observed across the gut microbiome, metabolomic signatures, molecular pathways, and clinical expression of coronary artery disease (CAD). In men, both healthy individuals and those with CAD display a gut microbial pattern enriched in bile-acid–associated taxa (such as Alistipes, Barnesiella, and Clostridia), accompanied by higher circulating bile acids, elevated indoxyl sulfate, acetate, visceral adiposity, and a pro-inflammatory metabolic profile driven by Western-diet patterns and higher testosterone levels. These features converge mechanistically through enhanced TMAO production, NLRP3 inflammasome activation, impaired TGR5 signaling, and endothelial dysfunction—translating clinically into an earlier onset of CAD, more frequent multivessel disease, and higher in-hospital mortality during acute myocardial infarction. In contrast, women, both healthy and with CAD, show enrichment in microbial taxa linked to tryptophan metabolism and secondary bile-acid production, alongside higher estrogen levels, preserved TMAO oxidation, lower inflammatory tone, and cardioprotective SCFA-related pathways. These biological differences align with a later onset of CAD in women, a lower prevalence of advanced or three-vessel disease, and reduced in-hospital mortality in acute events. Together, the figure summarizes how microbiome composition, hormonal environments, and metabolite profiles interact to shape distinct sex-specific trajectories of CAD development and severity.

The evidence included in this review presents several limitations. First, the number of available studies is limited (n = 11), and only one study directly examined the gut microbiota in the context of CAD with consideration of sex. Most studies were descriptive in nature and did not specifically explore the mechanistic links between gut microbiota composition and sex differences in CAD pathophysiology or outcomes. The limited number of studies available makes meaningful comparisons between them challenging. The discussion on the gut microbiota composition is only based on one study. Therefore, while our findings suggest potential sex-specific microbial patterns, it remains unclear whether these differences contribute directly to CAD pathophysiology or reflect secondary effects of other sex-related factors. Future mechanistic studies are required to validate causal relationships and clarify underlying biological pathways.

Furthermore, there is considerable heterogeneity across studies in terms of population characteristics, sample size, inclusion criteria, microbiome sampling and sequencing methodologies, metabolomic platforms, and clinical endpoints. These differences limit the direct comparability of findings between studies and currently preclude meaningful meta-analyses. This heterogeneity also complicates the identification of consistent sex-specific microbial or metabolic signatures in CAD, highlighting the need for standardized protocols and larger, well-characterized cohorts in future research. A key limitation of this study is the potential influence of well-established confounders on gut microbiome composition. Factors such as diet, medications, geography, socioeconomic status, and lifestyle can substantially impact microbial profiles. Without comprehensive control for these variables, observed sex-specific differences may partly reflect underlying systematic differences between male and female populations rather than true biological variation. This limitation should be considered when interpreting the findings and highlights the need for carefully controlled studies in future research. Although direct evidence linking gut microbiota to sex differences in CAD remains limited, we have integrated mechanistic insights from genetics, epigenetics, hormone signaling, and microbial metabolism to provide a comprehensive framework supporting this hypothesis.

An additional limitation is the near-complete absence of studies evaluating whether sex-specific microbial or metabolic profiles influence CAD progression, prognosis, or clinical outcomes. None of the included studies were designed to assess longitudinal changes, event rates, or treatment response in relation to gut microbiota differences between men and women. As a result, the current evidence does not allow conclusions about whether these microbial or metabolite variations translate into measurable differences in disease trajectory or outcomes.

Accordingly, the interpretations presented here should be regarded as hypothesis-generating rather than definitive, reflecting the early stage of sex-specific microbiome research in cardiovascular disease.

Not applicable.

Not applicable.

Caroline Chong-Nguyen reports research grants from the French Society of Cardiology, the Swiss Life Foundation and the Peter Bockhoff Foundation, travel and educational grants from Abbott as well as consulting and proctoring for Abbott without personal remuneration. Thomas Pilgrim reports research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Swiss Polar Institute, the Bangerter-Rhyner Foundation, the Mach-Gaensslen Foundation, and the Monsol Foundation. Research, travel or educational grants to the institution without personal remuneration from Biotronik, Boston Scientific, Edwards Lifesciences, and ATSens; speaker fees and consultancy fees to the institution from Biotronik, Boston Scientific, Edwards Lifesciences, Abbott, Medtronic, Biosensors, and Highlife. Bahtiyar Yilmaz declares no conflict of interest. Yvonne Döring declares no conflict of interest. Rubén Fuentes Artiles declares no conflict of interest.

All data generated or analysed during this study are included in this published article and its supplementary information files.